1. Field of the Invention
The present invention relates to process for preparing crystalline 3-chloromethyl-3-cephem derivatives, and particularly to process for preparing 3-chloromethyl-3-cephem derivatives expressed by Chemical Formula (2) in crystal form, which are useful as an intermediate for synthesizing 3-chloromethyl-3-cephem antibiotics.
where R2 and R3 each represent a substituted or unsubstituted aromatic hydrocarbon group.
2. Description of the Related Art
The 3-chloromethyl-3-cephem derivatives expressed by Chemical Formula (2) are known as useful intermediates for synthesizing cephalosporin antibiotics, as disclosed in, for example, Japanese Unexamined Patent Application Publication Nos. 59-172493, 58-72591, 60-255796, 61-5084, 1-156984, and 1-308287, and International Patent Application Publication Nos. WO 99/10352 and WO 98/58932.
For the preparation of a 3-chloromethyl-3-cephem derivative expressed by Chemical Formula (2), for example, the acetoxy group of the acetoxymethyl group at the 3-position of a 3-acetoxymethylcephalosporin derivative is halogenated in the presence of a Lewis acid, such as boron trichloride (Tetrahedron Lett., p. 3991, 1974). In another process, a 2-azetidinone derivative prepared from penicillin G may be chlorinated by electrolysis and, then, cyclized to form a cephem derivative with a base (Tetrahedron Lett., 23, p. 2187, 1982). Also, Japanese Unexamined Patent Application Publication No. 4-66584 has disclosed a process in which a 7-substituted amino-3-hydroxymethyl-3-cephem-4-carbonate ester expressed by Chemical Formula (3) is allowed to react with a chlorinating agent in the presence of an alkaline-earth metal carbonate according to Reaction Formula (1):
Japanese Unexamined Patent Application Publication No. 58-74689 has disclosed a process in which an azetidinone derivative expressed by Chemical Formula (1a) is allowed to react in an organic solvent in the presence of a base according to Reaction Formula (2):

Among these processes, the process proposed by Japanese Unexamined Patent Application Publication No. 58-74689 provides 3-chloromethyl-3-cephem derivatives in oil form. In this process, dimethylformamide, which dissolves both the starting material azetidinone derivative expressed by Chemical Formula (1a) and the reaction product 3-chloromethyl-3-cephem derivative, is used as a reaction solvent, and the starting material is allowed to react with a base, weak alkaline ammonia or ammonia water, while the reaction product is prevented from being decomposed.
In this process, an alcohol, such as methanol, ethanol, or 2-propanol, may be used as the reaction solvent, and a metal hydroxide, such as strongly basic sodium hydroxide or potassium hydroxide, may be used as the base. However, since the alcohol does not dissolve the reaction product 3-chloromethyl-3-cephem derivative, the use of the alcohol does not provide the reaction product in oil form. In addition, the alcohol reacts with the base to produce water, which dissolves the base to increase the pH of the reaction system, that is, to make the reaction system alkaline. Consequently, the reaction product 3-chloromethyl-3-cephem derivative is decomposed by the alkali and thus, the yield is reduced.
Furthermore, 3-chloromethyl-3-cephem derivatives include a chlorine atom in their molecule, and are, consequently, instable in oil form. For example, the 3-chloromethyl-3-cephem derivatives release hydrochloric acid to decompose themselves during storage at room temperature, thus degrading the quality. Accordingly, such a 3-chloromethyl-3-cephem derivative is desired that is relatively stable for a long time in moderate conditions.
A process has been proposed in which a crystalline 3-chloromethyl-3-cephem derivative is prepared from an oil form.
For example, International Paten Application No. WO 99/10352 has proposed a process for preparing a crystalline 3-chloromethyl-3-cephem derivative by crystallizing an oily 3-chloromethyl-3-cephem derivative dissolved in dimethylformamide, with a cold alcohol or an alcohol-water mixture.
However, this process includes a complicated step of crystallizing an oily 3-chloromethyl-3-cephem derivative that has once been synthesized, and is thus disadvantageous in industrial production.